Practical microenvironment classification in diffuse large B cell lymphoma using digital pathology

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous B cell neoplasm with variable clinical outcomes influenced by both tumor-derived and lymphoma microenvironment (LME) alterations. A recent transcriptomic study identifies four DLBCL subtypes based on LME characteristics: germinal center (GC)-like, mesenchymal (MS), inflammatory (IN), and depleted (DP). However, integrating this classification into clinical practice remains challenging. Here, we utilize deconvolution methods to assess microenvironment component abundance, establishing an LME classification of DLBCL using immunohistochemistry markers and digital pathology based on CD3, CD8, CD68, PD-L1, and collagen. This staining-based algorithm demonstrates over 80% concordance with transcriptome-based classification. Single-cell sequencing confirms that the immune microenvironments distinguished by this algorithm align with transcriptomic profiles. Significant disparities in overall and progression-free survival are observed among LME subtypes following rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP with targeted agents (R-CHOP-X) immunochemotherapy. LME subtypes differed from distinct immune escape mechanisms, highlighting specific immunotherapeutic targets and supporting application of this classification in future precision medicine trials.